22 {Conrarsonox raow mz Daraxraznr or Canaierny xp Canuncat Exonenenine or mux Univansiry or Pesyer.vaxa] ANALOGS OF EPHEDRINE AND ADRENALINE CONTAINING ‘THE MORPHOLINE NUCLEUS AND SOME OF ‘THEIR ESTERS NATHAN RUBIN axp ALLAN R. DAY Received August 6, 1989 mxrmopucriox Since the advent of cocaine as a local anesthetic, « lange amount of literature has appeared on the synthesis of related compounds. The pur- pose of most of this work was to obtain active local anesthetics which would be less toxie than cocaine. ‘These aims have been accomplished to some extent and there are now available a large number of compounds, mostly benzoates or p-aminobenzoates of N-substituted amino alcohols, which compare favorably with cocaine. In general, however, they lack: the vasoconstrcting power shown by cocaine and consequently must be used in conjunction with adrenaline. The latter, by decreasing the rate st which the anesthetic is carried away from the point of injection, permite the use of lower concentrations and also acts as a hemostatic agent Attempts have been made by several workers to combine structures «essential for vasoeonstrietion and structures essential for anesthetic activity with the hope that the physiologica! effects might be cumulative. In feoera,preseraeiiy hs bee found ia compaunds pomesing the spoupng Ar-C—C-N and loa neste activity in compounds con- Ld taining the grouping Ar—CO—O—C—C—N—R. Most of the com- I younds prepared upto this time tat contain both ofthe required groupings have not been entirely satisfactory. This work has been reviewed in two excellent papers by Hartung (1) and by Alles and Knoefel (2). More recently, Coles and Loth (8) prepared some aromatic esters of N-B-ydroxyethyl- and N-r-hydroxypropyl-_ac-tetrabydro-B-naphthyl- ‘amine. Although ac-tetrahydro-8-naphthylamine has been shown to have definite pressor action, the new derivatives were lacking in this property. Osborne (4) reported that the synthesis of a-(3 ,4-dihydroxyphenyl)-6- (p-aminobenzoyl-$-diethylaminoethanol)-a-ethanone hydrochloride (epi- apounds, «no aleobols, 1, they lack tly must be Jing the rate ion, permits agent, ve structures retie activity sulative. In sssessing the pounds con- af the com ed groupings iewed in two @. Mic esters of >-Bnaphthyl- hown to have his property oxypheny bloride (ei ANALOGS OF EPHEDRINE AND ADRENALINE 55 caine) produced a drug which combines both local anesthetic and vaso pressor action. It does not seem possible to draw any dofinite conclusions from the above work, since the evidence for the various compounds does not agree very well. In some eases both anesthetic and pressor activity were re- ported and in other cases for closely related compounds pressor activity was lacking. The fact that none of these compounds appears to be in general use might indicate that the problem has by no means been solved. Since certain morpholino compounds have been shown to possess local anesthetic action (3), it was planned to condense morpholine with struc- tures known to exert vasopressor action, hoping to obtain compounds of medicinal value, Therefore morpholine was condensed with phenacyl bromide, a-bromopropiophenone, p-hydroxyphenacyl chloride, 3,44di- hydroxyphenacyl chloride and phenylethyl bromide, to yield amino ketones which in turn were catalytically reduced to the corresponding, carbinols. Where R equals H, the side chain CH:.CHy CHy-CHy \ arcoc. x 0 ACHOH.CH.N” ‘o oN 7 roN 7 Rk CH:-CHY R “CH,.CH, ReH,CH Ar=CiH, HOCH, 3,4-(HO)CH js structurally similar to adrenaline and where R equals CHs, the side chain is similar to that found in ephedrine. The condensation product from phenylethy! bromide, of course contained no alcohol group in the side chain. Since aromatic esters of amino alcobols usually possess anesthetic sctivity. the benzoates of I-phenyl-2-morpholinoethanol-1 and 1-phenyl- 2-morpholinopropanol-1 were prepared as well as the cinnamate of the ‘ethanol derivative, Magee and Henze (6) have recently prepared a series of Salkylamino hydantoins, Certain bydantoins substituted in the five position have been shown to possess hypnotic activity. Since four new amino ketones were prepared in the course of the present work, it was thought that the corresponding hydantoins might be of some interest. Attempts to prepare these hydantoins by the Bucherer method (7) were successful only in the case of «-morpholinoacetophenone from which S-phenyl-5-morpholino- ‘methyl hydantoin was obtained. These compounds are being tested and the pharmacological report will be made later. EXPERIMENTAL Analysis Tae semi-miero Kijeldabl method was used for the nitrogen determina tion. The distillate was absorbed ia 15 re, of 4% boric acid solution and titrated toa methyl-red endpoint according to the method of Meeker and Wagner (8)56 NATHAN RUBIN AND ALLAN B. DAT Preporation of catalyet-~The catalyst employed in most cases was 10%, palladium ‘on charcoal prepared according to the method of Hartung (0). The 20% palladium ‘on charcoal catalyst was prepared similarly. In all eases the extalyat was shaken lunder an atmosphere of hydrogen until no more gas was absorbed, immediately before the introduction of the sample. ‘Preparation of phenacyl bromide —To 30g. (0.25 male) of acetophenone dissolved in 36-40 ce of plaial acetic acid, 40g, (0.25 mole) of bromine was added all at once. ‘The dask was then immediately attached toa reflux condenser suitably connected for the absorption of hydrogen bromide, shaken in order to make the mixture homo- ‘Eeneoun and then allowed to stand. After a few minutes a vigorous reaction took place with the evolution of hydrogen bromide. The straw-colored liquid was poured into mixture of ice and water and was permitted to stand approximately ooe hour. ‘At the end of this time the solid was removed by filtration and the oil well pressed ‘out. ‘The solid was then immediately recrystallized from 95% sleohol. Yields of 25-80 , (60-60%) of pure product melting at 49.5-80" were obtained. This method ia similar to that employed by Schmidt (10) for the preparation of «-bromopropiophe- one. ‘The method of Rather and Reid (11) gave lower yields of a considerably darker product. ‘Preparation of a-bromopropiophenone.—This was prepared similarly to the phe- ‘The reaction mixture after further ‘Preparation of p-hydrosyphenacyl choride.—Thin waa prepared sccording to ‘Tutin, Caton and Hann (14), using ligroin, however, instead of earboo divulfide as the solvent. The use of ligroin greatly reduced the amount of gum formed, Thirty rama (0.277 mole) of anisole and 36 g. (0.818 mole) of chloroncetyl ebloride were ‘Gimolved in 300 oc. of ligroin. To the rapidly atired solution, 75 g. (0.56 male) of ‘anhydrous alumioum chloride was added over period of three-quarters of an hour, ‘the mixture permitted to stand one hour and then 45 . (04 mole) more of aluminum ‘cbloride was added in about balf an hour. ‘The resulting mixture wan heated for four hours on the water-bath. At the end ofthis time the solvent was removed by dintllation and the eomplex was decomposed by ice, fllowed by 30 ec. of concen- ‘trated hydrochloric acid. ‘The mixture was taken up in ether and extracted frat ‘with 6% ammonium carbonate solution and then with 109 sodium carbonate ealu- lon. Acidification of the sodium earbonate extract alter treatment with charcoal yielded 17.0, of « yellow product. It may be recrystallized from methyl aleobol; mp. M7, ‘Preparation of $,4-dihydrosyphenecyl chloride This was prepared essentially sccording to Mannich and Hahn (18). "A mixture of 50g. (0.454 mole) exch of eate- ‘hol, monochloroscetic acid (0.58 mole) and phosphorus oryehloride (0.825 mole) swas placed in a large Sask fitted with a refux condenser and a tube to lead away Ihydrogen chloride. Tt was heated on a hot plate until gas was evolved and then immediately removed from the plate. The reaction proceeded spontaneously. By ‘voiding too long heating at this point a better yield was obtained. At the com- pletion ofthe reaction, $00 ec. of boiling water was added to distolve the mass, and the solution allowed to stand in an ice chest for two days. The product was then ‘tered and dried. Yields averaged from 40-47 g. (52-61%). Reeryaalization ‘rom bot water, employing charcoal for decolorisstion, yielded slight colored prod- ‘uct melting at 173"ANALOGS OF EPHEDRINE AND ADRENALINE 37 Preparation of -(-phenylthy!)-morpholine hydrochloride —To 18.5 g, (0.1 mole) of phenylethyl bromide disolved in 30 ee. of alcohol was added I7.4g. (0.2 mole) of morpholine dissolved in 2S cc. of alcohol. The mixture was refed for two hours fon a water-bath, and then cooled, whereupon a crystalline precipitate separated. ‘The reaction mixture was diluted with one and one-balf times ita volume of ether, allowed tostand eshort time and was then filtered, The crystalline residue, consist- ing of morpholine hydrobromide, was washed well with ether and the washings added tothe trate, Dry hydrogen chloride was passed into the cooled Sltrate and yielded. 1775 g. (78%) of crystalline hydrochloride. Recryetallisation from bot aleobol agave a colorless product melting at 246° (cor.). This compound has been reported (6) a melting st 238" Anal. Cale'd for CuHuCINO: N, 6.15; Cl, 18.87. Found: N, 5.98; Cl, 18.64 Preparation of -morphalinoacelophenone hydrochloride. —To 9.95 g. (0.05 mole) of phenacyl bromide mixed with 30-40 ce. of alcobol and cooled to 0°, 8.7 g. (0.1 mole) ‘of morpholine was lowly added with stirring, the addition being made at rate such ts to maintain the temperature below 15°. ‘The mixture was then allowed to warm up toroom temperature and allowed to stand fortwo hours at the end of which time 180ce.ofether wasadded. After standing overnight, it was Sltered, and the erystal- line morpholine hydrochloride wan washed with ether, which was added to the Strate, ‘The amino ketone hydrochloride was precipitated by passage of dry hydro- igen chloride over the ether. After collecting on a Alter, washing with ether, and drying, 95-11 g. 79-91%) of crystalline material was obtained. Recrystallisation {rom hot alcohol yielded a colorleas product melting with decomposition at 222-228" (corr.). ‘This compound haa just been patented and reported as melting at 215-214" vith decomposition (12) ‘Anal. Cale'd for CyifyCINOs: N, 5.0; Cl, 4.68, Found: N, 576; Cl, 1460 ‘This compound may also be prepared in 70-75% yield by refluxing one equivalent of amine with one equivalent of phenacyl bromide in alcohol solution in the presence of a aight exceas of anhydrous potassium earbonste. ‘The free base waa obtained nly as an impure ol. Preparation of evmorpholinopropiophenone hydrochloride —This wan prepared imilarly tothe ermorpholinoacetophenone hy drochloride in yelda averaging 60-85%, employing either two equivalenta of morpholine or one equivalent of morpholine ‘with anhydrous potassium carbonate. Recrystalisation from hot aleohol yielded a colorless product melting at 224° (corr) with decomposition. This compound bas just been patented and reported aa melting with decomposition at 224" (12) “Anal. Cale'd for CubluCINOs: N, 5.48; Cl 13.98 Found: N, 542; Cl, 1878 Preparation of w-morphalino-p-hydrosyacelophenone.—To 6 g. (0.095 mole) of p-bydroxyphenscyl chloride in 10ce. of alcobol, 6.124, (0.07 mole) of morpholine was Slowly added, maintaining the temperature below 16°. Ten cubie centimeters of ther was added during the addition in order to keep the mixture {rom becoming solid. "More ether was then added and the mixture allowed to stand overnight. It was then filtered and dried. The dried product was auspended in water to dissolve ‘out the morpholine hydrochloride. The residue was filtered, washed well with water ‘and dred, yielding 7.0. (00%) of product. Recrystalisation from aleobol, using a ‘mnall amount of charcoal, yielded colorleas needles of melting point 201-201.7° (cor) ‘Anal. Cale'dfor CyHisNOy: N, 633. Found: N, 6.13.58 NATHAN RUBIN AND ALLAN R. DAY ‘The hydrochloride was prepared by suspending the base in alcohol and passing. hydrogen chloride nto the solution, It melta with decomposition at 242-243" (corr). ‘Anal. Cale'd for CuByCINO,: N, 844; Cl, 18.76. Found: N, 5.4; Cl, 18.79 Preparation of wnmorpholino-$,4-dihydrozyaceiophenone.—This was prepared similarly to the p-hydroxyacetophenone derivative from morpholine and 3,4-di- bydroxyphensey! ebloride. The compound was obtained in 85-00% yields. The base was best reeryatallized from 80% alcool. ‘The colorless product melted at 201° (cor.) with decomposition “Anal. Cale'd for CuHuNO,: N, £88. Found: N, 5.84 ‘The hydrochloride was obtained by passing hydrogen chloride over an aleoholic ‘suspension of the base. The hydrochloride decompoues at 24-225° (cor. “Anal. Cale'd for CuBuCINO.® N, 8.12; Cl, 1296. Found: N, 5:05; Cl, 125 Preparation of I-phenyl--morphalinocthanol-l hydroehloride-—This compound vas prepared by the entalytic reduction of the corresponding ketone in 95% alcohol solution, employing 10% palladium on charcoal ax thecatalyet (2). Ten gramsof the sino ketone hydrochloride was added to 200 ce. of alcohol containing 4.5 g. of dry hydrogen chloride and8.3g. of catalyst. ‘This was then shaken under an atmosphere ‘of hydrogen in an apparatun similar to that of Schaefer (12) until the calculated volume of hydrogen had been absorbed. At the completion of the reduction the solution was filtered free of catslyat and evaporated to « small volume. After cooling, twice the volume of ether was added, and the mixture waa allowed to stand ince for complete precipitation. After fltration, washing with a amall amount of ther and drying, 8 g. (81.8%) of product was obtained. Reerystalization from Dot alcobol yielded a clorles product melting at 188-188.7° (ort). ‘Anal. Cale'd for CuHCINOx: N, 575; Cl, 14.56. Found: N, 568; Cl, 14.38, Preparation of I-phenyl--morpholinocthanol-1.—This compound was prepared from the hydrochloride by the addition of dilute ammonia or dilute nodium hydroxide to ao aqueous solution of the hydrochloride. Tt wan reeryatallined from dilute p. 80,0-813° (corr). by catalytic reduction, in 80-85% yyielda, After the reduction, due to the leeer solubility of the propanol derivative, it was necestary to filter the solution hot. Reeryatallization from sleobol yielded « ‘colorless product melting at 25° (corr). ‘Anal, Cale'd for CylnCINO,: N, 5.44; Cl, 18.87. Found: N, 6.45; Cl, 1380. Preparation of 1-phenyl-t-morpholinopropanol-1.—This was prepared from the hydrochloride by the addition of dilute ammonium hydroxide or dilute sodium, hydroxide. A pure product, mp. 73-73.5" corr.) was obtained by reerystallization {from dilute aleohol ‘Anal, Cale'd for CuBisNOn: N, 633, Found: N, 62. Preparation of 1-(p-hydrosyphenyl)--morpholinotthanol-l hydrochloride —Thia was prepared by eatalytic reduction of the corresponding ketone hydrochloride in ater solution employing 20% palladium on charcoal as theeatalyst. After filter 3 the eatalyat, the aqueous solution Was evaporated almost to dynes, cooled, a Acetone added. The compound was obtained in 78% yield. Recryatallieation of[ANALOGS OF EPHEDRINE AND ADRENALINE i te compound from alcool yielded clos produtt melting with decomposition stim or) Tr ld fr CuBix1NOr: N, 838; C1865 Found: 8,698; 1887. Preparation of "1, tdigtrsyphenl-$morpolisothanet hye, — mer peparedinsatiy tthe ayony derive employing 1 pede og sal Marthe removal ol hecaalyet by retin thesluton ts eaperiog teeta Grade ean of 89-08% were obttned.Reergvallaaion row aco, wedTRer and employing chao led a colriee produt dovmpeing 12 cor). : ‘Anal. Cale’d for CisHisCINO«: N, 5.08; Cl, 12.86. Pounds 8,498; C), 1258 Preparation of te bencote of Sophnp--morpotinoana!hydrecride — eating the tine asoh hyrochorde wih exe bentyl chondeen«Hetn- balnforthresbore led ochane complete esteem, Bensoystion stomped Denatne sluon, beating unl wo more hydrogen chloride wat evlve, ced tho apparent unehangd tine soba bytecode: Thu tar was bart po- pared Oy ating 0g {0014 mn) af he eine leas hytocleriae with 8c {09 mot) of benany chlrde for three howe st 15010" aan rte At the {odo hin inte suton wan coved ether weeded nd te iar alowed to ttandoveragh ‘The eryealie prodt we then ered, washedrapetely with Cther and ded Recrywalizaton fom bot lecol aod eter pled 00% o Colerln predact meting ot 1.8 176 (cre). “dna.” Caled for CutixINOv: N, 85; 1008. Found: 8,991,010 reparation af he eintamate of t-phny--morphlnaanl!hyéechlrie — To3S6q (2 ole) of cine) cAlrdefnelved in 3 eof dy speve wen Maeda. (0018 mol) of Ipbegl-o-mocpelinontaael- sled i 30 Sf dy xylene, ‘This istry wan honed ina l-bath mistaned at 10" or two Soar, AL te end of thie im the rencion mints wa ones tered ad Product wahed with eer. The yield wae 438g G7). Recrwtalisaon from eotl led clrem product sling t 20-0). “Anal Cue’ for Cus ONO,. N29) Cl, 2.8 Found: N, 808; 940, Preparation ofthe beats ofI-phny-marphlnopropanl-! hydride — ‘The eter wan oblaised In 8% ero yield by hosting the amine aeabal hydro- ‘hind ith exes beoroylehorideforSve hore to 1125 eat othe toa ‘eivative, Hecrgvalaaion rm bot alnbe and ee yieed cool produet telnet 310-210 err} “Ano. Calcd or Colle CINOs: N,357;0,980._ Found: N, 404,03, 1023. Preprsios of pheg-omerpalinonsigt hydonien Thon. Bydaaton was pepured seoring tote met of cheer and Stsaes Five gama (O22 Tal) of evmorpiincaeeaphenone hydrochloride wan cnsicd in Sco af SO% Tico, To tin wat added 2g (040 mle) of potanum cprsde and 8 g (0.08 Sate) af pondered umononizm carbonate "This mitare was chan well and bested ta tn water-uih for eghtand one-half our, tniatining te bath tween 0 Needle sariedtstpernte atthe end of two horn, ‘The mivtare wer lowed took dlutedyithqeterandfltered, ‘Thecradeyiid war 8a (9%), Reryatal> nation rom hot lesb eed colores nendles lng at 20-244" (crt) “Gna. Cale dtor QateNiby 81898. Found: 83817. =« NATHAN RUBIN AND ALLAN B. DAY ‘The hydrochloride of this base was prepared by suspending the base in aleohol ‘and passing in dry hydrogen chloride. Recryntallization from alcobol yielded = 2 206* (corr) with decomposition. for CuHusCINiOs: N, 18.48; Cl, 1.37. Found: N, 1840; Cl, 11.28. Attempts to prepare the bydantoins of e-morpholinopropiophenone, w-morpbo- lino-p-hydroryacetophenone and wmorpholine-3,4-dibydroryscetophenone using ‘the method of Bucherer (7) failed. soiaaRY 1. The following amino ketones, w-morpholinoscetophenone, -morpho- linopropiophenone, w-morpholino-p-hydroxyseetophenone and w-mor- pholino-8, 4-dihydroxyscetophenone, have been prepared. 2. The corresponding carbinols have been prepared by catalyticredue- tion employing palladium on charcoal as the catalyst. 3. The benzoates of I-phenyl-2-morpholinoethanol-l and I-pheny!-2- ‘morpholinopropanol-1, as well as the cinnamate of the ethanol derivative, have been prepared. 4. The compound S-phenyl-S-morpholinomethyl bydantoin bas been prepared by the method of Bueherer. Attempts to prepare hydantoins of the other amino ketones failed. Punapecrms, Pa. REFERENCES (1) Hanrowo, Chem. Ree, 9,889 (1981). (@) Atine axp Kwonret, Arch, Internat. de Pharmacodynamie etd, therap., 47, 98 1958), (@) Cours ax Lorn, J. Am. Chem, So., B, 1989 (188). @) Ossomse, Science, 85, 105 (1937). () Ganowen axp Hanson, J. Am. Chem. Soe, 8, 2763 (1931); Ganowes, Cranes ‘an Seu, ibid, 66, 2999 (1983); Ganpinex ax Hanaet, ibid, 68, 1360 (1908); Lurrian ax Bunt, sid., 66, 365 (1995); Surrw ax Poutano, ‘bid, 69,131 (1987). (© Maore aso Herr, ibid., €0, 2148 (1838), ©) Bocuznen sxp Srenven, J. prokt. chem., 140,201 (1934). @) Merxen avo Waowrn, Ind. Bng. Chem. Anal. Bd. 6,306 (1933). (©) Haxrona, J. Am. Chem. Soc., 60, 8870 (1928). (10) Someroz, Ber, 22, 251 (1880). (11) Ravuen avo Rasp, J. Am. Chem. Soe., 41,7 (1919). (12) German Patent 667,386, November, 1038, (13) Scuazren, Ind. Eng. Chem, Anal. Ed., 2, 115 (1990). (14) Torx, Catow ax Han, J. Chem. Soe, 6, 2118 (1909). (15) Masnutem aso Has, Ber, 4, 1648 (911). (16) Leyruzn ax Voursizs, J. Am. Chem. Soe, 0,896 (1938).CONTENTS ‘Nowser 1, Jawoany, 1940 On 1,2 and 1,4-Addition. IV. Nitrogen Tetroxide and Isobuty- lene. Arthur Michael and G. H. Carlson. 1 On 1,2 and 1,4-Addition, V. Nitrogen ‘Tetroxide and Tetra- methylethylene. Arthur Michael and G. H. Carlson. “4 Sulfur Studies. XV. The Synthesis of Alkane-sulfonic Acids and Certain Derivatives. P. H. Latimer and R. W. Bost a ‘The Rate of Dissociation of Pentaarylethanes, W. B. Bachmann and Gerald Osborn... 9 ‘The Reduction of 1,2,3-Bensotriasole and ite N-Methyl Derivatives by Sodium in Liquid Ammonis. Norman 0. Cappel and W. Conard Fernelius 40 ‘Allenes. I. The Preparation of l-Cyclohexyl-2,3-pentadiene. Fred Acree, Jr., and F. B. LaForge..... ‘Analogs of Ephedrine snd Adrenaline Containing the Morpholine Nucleus and Some of Their Esters. Nathan Rubin and Allan R. Day. ‘The Action of Grignard Reagents on Heavy Metal Salte. Ill. Mixed Grignard Reagents and Silver Bromide. Lionel Joseph with John H. Gardner. : a ‘Acylation of Aldoximes. III. The Configuration of Diphenyl- carbamy! and Picryl Ether Derivatives Prepared from syn Aldoximes. Gertrude Vermillion, A. B. Rainsford and Charles R, Houser recesses cee 68 ‘The Acylation of Aldoximes. IV. ‘The Benzoylation of ayn, and anti ine eee et a eee Howser 6 ‘Nuuser 2, Manca, 1940 Properties of the Thiomethylene Radical. II. The Behavior with Chlorine and Water. S. W. Lee and Gregg Dougherty a Calculation of the Number of Stereoisomere in Carbon Chain Com- pounds. Gerald Z. K. Branch and Terrell L. Hil 86 A New Synthesis of Dinitroparaffine. L. W. Seigle and H.B. Hass... 100 Oressothmiun Compounds, 1. Meth al partion. Arid V. Grosse and Julian M. Mavity..... 106 ii